This invention relates to pyrimidine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
The enzyme cyclooxygenase (COX) has recently been discovered to exist in two isoforms, COX-1 and COX-2. COX-1 corresponds to the originally identified constitutive enzyme while COX-2 is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. Prostaglandins generated by the action of COX have both physiological and pathological roles. It is generally believed that COX-1 is largely responsible for the important physiological functions such as maintenance of gastrointestinal integrity and renal blood flow. In contrast the inducible form, COX-2, is believed to be largely responsible for the pathological effects of prostaglandins where rapid induction of the enzyme occurs in response to such agents as inflammatory agents, hormones, growth factors and cytokines. A selective inhibitor of COX-2 would therefore have anti-inflammatory, anti-pyretic and analgesic properties, without the potential side effects associated with inhibition of COX-1. We have now found a novel group of compounds which are both potent and selective inhibitors of COX-2.
The invention thus provides the compounds of formula (I) 
and pharmaceutically acceptable derivatives thereof, in which:
R1 and R2 are independently selected from H, or C1-6alkyl;
R3 is C1-6alkyl or NH2;
R4 is H or C1-6alkyl;
A is a 5- or 6-membered aryl, or a 5- or 6-membered aryl substituted by one or more R5;
R5 is halogen, C1-6alkyl, C1-6alkyl substituted by one or more F, C1-6alkoxy, C1-6alkoxy substitued by one or more F, SO2NH2 or SO2C1-6alkyl; and
n is 1 to 4.
By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, solvate, ester or amide, or salt or solvate of such ester or amide, of the compounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
It will be appreciated by those skilled in the art that the compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds. Of particular interest as such derivatives are compounds modified at the benzenesulphonamide function to provide metabolically labile benzenesulphonamides. Acylated benzenesulphonamide derivatives are of especial interest.
It will be appreciated by those skilled in the art that the pharmaceutically acceptable derivatives of the compounds of formula (I) may be derivatised at more than one position.
It will be further appreciated by those skilled in the art that benzenesulphonamide derivatives of formula (I) may be useful as intermediates in the preparation of compounds of formula (I), or as pharmaceutically acceptable derivatives of formula (I), or both.
It will be appreciated that, for pharmaceutical use, the salts referred to above will be the physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I) and the physiologically acceptable salts thereof.
Suitable pharmaceutically acceptable salts include: acid addition salts formed with inorganic or organic acids, preferably inorganic acids, e.g. hydrochlorides, hydrobromides and sulphates; and alkali metal salts, formed from addition of alkali metal bases, such as alkali metal hydroxides, e.g. sodium salts.
The term halogen is used to represent fluorine, chlorine, bromine or iodine.
The term xe2x80x98alkylxe2x80x99 as a group or part of a group means a straight or branched chain alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group.
The term 5-membered aryl means an aryl selected from the following: 
The term 6-membered aryl means aryl selected from: 
It will be appreciated by those skilled in the art that when R1 and R2 in formula (I) are different the corresponding compounds contain at least one chiral centre, by virtue of the asymmetric carbon atom defined thereby, and that such compounds exist in the form of a pair of optical isomers (i.e. enantiomers).
It is to be understood that the present invention encompasses all isomers of the compounds of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures).
In one aspect of the invention R1 and R2 are independently selected from H or methyl. In another aspect R1 and R2 are both H.
In another aspect of the invention R3 is C1-6alkyl, such as C1-3alkyl (e.g. methyl).
In another aspect of the invention, R4 is H or C1-3alkyl, such as methyl.
In another aspect of the invention A is selected from 
and A is unsubstituted or substituted by one or two R5 (e.g. one R5).
In another aspect of the invention A is selected from 
In another aspect of the invention R5 is halogen (e.g. F), C1-3alkyl (e.g. methyl), C1-3alkyl substituted by one to three F (e.g. CF3), C1-3alkoxy (e.g. methoxy), C1-3alkoxy substituted by one to three F (e.g. OCHF2 or OCF3), or SONH2.
In another aspect of the invention R5 is halogen (e.g. F) or C1-6alkoxy, such as C1-3alkoxy (e.g. methoxy).
In another aspect of the invention n is 1 to 3 (e.g. 1).
It is to be understood that the invention covers all combinations of particular aspects of the invention as described hereinabove.
Within the invention there is provided one group of compounds of formula (I) (group A) wherein: R1 and R2 are independently selected from H or methyl; R3 is C1-6alkyl, such as C1-3alkyl (e.g. methyl); R4 is H or C1-3alkyl, such as methyl; A is selected from 
and is unsubstituted or substituted by one or two R5 (e.g. one R5); R5 is halogen (e.g. F), C1-3alkyl (e.g. methyl), C1-3alkyl substituted by one to three F (e.g. CF3), C1-3alkoxy (e.g. methoxy), C1-3alkoxy substituted by one to three F (e.g. OCHF2 or OCF3), or SONH2; and n is 1 to 3 (e.g. 1).
Within the invention there is provided another group of compounds of formula (I) (group B) wherein: R1 and R2 are independently selected from H or methyl; R3 is C1-6alkyl, such as C1-3alkyl (e.g. methyl); R4 is H or C1-3alkyl, such as methyl; A is selected from 
R5 is halogen (e.g. F), C1-3alkyl (e.g. methyl), C1-3alkyl substituted by one to three F (e.g. CF3), C1-3alkoxy (e.g. methoxy), C1-3alkoxy substituted by one to three F (e.g. OCHF2 or OCF3), or SONH2; and n is 1 to 3 (e.g. 1).
Within the invention there is provided another group of compounds of formula (I) (group C) wherein: R1 and R2 are independently selected from H or methyl; R3 is C1-6alkyl, such as C1-3alkyl (e.g. methyl); R4 is H or C1-3alkyl, such as methyl; A is selected from 
R5 is halogen (e.g. F) or C1-6alkoxy, such as C1-3alkoxy (e.g. methoxy); and n is 1 to 3 (e.g. 1).
In another aspect of the invention, R1 and R2 in the compounds of groups A, B and C are both H.
In another aspect the invention provides the following compounds:
4-[4-(methylsulfonyl)phenyl]-N-(pyridin-4-ylmethyl)-6-(trifluoromethyl)pyrimidin-2-amine;
4-[4-(methylsulfonyl)phenyl]-N-(pyridin-3-ylmethyl)-6-(trifluoromethyl)pyrimidin-2-amine;
4-[4-(methylsulfonyl)phenyl]-N-(pyridin-2-ylmethyl)-6-(trifluoromethyl)pyrimidin-2-amine;
4-[4-(methylsulfonyl)phenyl]-N-(phenylmethyl)-6-(trifluoromethyl)-2-pyrimidinamine;
N-(4-methoxybenzyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-amine;
N-(4-fluorobenzyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-amine;
and pharmaceutically acceptable derivatives thereof.
Compounds of the invention are potent and selective inhibitors of COX-2. This activity is illustrated by their ability to selectively inhibit COX-2 over COX-1.
In view of their selective COX-2 inhibitory activity, the compounds of the present invention are of interest for use in human and veterinary medicine, particularly in the treatment of the pain (both chronic and acute), fever and inflammation of a variety of conditions and diseases mediated by COX-2. Such conditions and diseases are well known in the art and include rheumatic fever; symptoms associated with influenza or other viral infections, such as the common cold; lower back and neck pain; headache; toothache; sprains and strains; myositis; sympathetically maintained pain; synovitis; arthritis, including rheumatoid arthritis; degenerative joint diseases, including osteoarthritis; gout and ankylosing spondylitis; tendinitis; bursitis; skin related conditions, such as psoriasis, eczema, burns and dermatitis; injuries, such as sports injuries and those arising from surgical and dental procedures.
The compounds of the invention are also useful for the treatment of neuropathic pain. Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them. Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; neuralgia, such as post-herpetic neuralgia and trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. These conditions are difficult to treat and although several drugs are known to have limited efficacy, complete pain control is rarely achieved. The symptoms of neuropathic pain are incredibly heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain. In addition, there is pain associated with normally non-painful sensations such as xe2x80x9cpins and needlesxe2x80x9d (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
The compounds of the invention are also useful for the treatment of other conditions mediated by COX-2.
For example, the compounds of the invention inhibit cellular and neoplastic transformation and metastatic tumour growth and hence are useful in the treatment of certain cancerous diseases, such as colonic cancer and prostate cancer. The compounds of the invention are also useful in reducing the number of adenomatous colorectal polyps and thus reduce the risk of developing colon cancer. The compounds of the invention are also useful in the treatment of cancer associated with overexpression of HER-2/neu, in particular breast cancer.
Compounds of the invention also prevent neuronal injury by inhibiting the generation of neuronal free radicals (and hence oxidative stress) and therefore are of use in the treatment of stroke; epilepsy; and epileptic seizures (including grand mal, petit mal, myoclonic epilepsy and partial seizures).
Compounds of the invention also inhibit prostanoid-induced smooth muscle contraction and hence are of use in the treatment of dysmenorrhoea and premature labour.
Compounds of the invention are also useful in the treatment of liver disease, such as inflammatory liver disease, for example chronic viral hepatitis B, chronic viral hepatitis C, alcoholic liver injury, primary biliary cirrhosis, autoimmune hepatitis, nonalcoholic steatohepatitis and liver transplant rejection.
Compounds of the invention inhibit inflammatory processes and therefore are of use in the treatment of asthma, allergic rhinitis and respiratory distress syndrome; gastrointestinal conditions such as inflammatory bowel disease, Crohn""s disease, gastritis, irritable bowel syndrome and ulcerative colitis; and the inflammation in such diseases as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin""s disease, sclerodoma, type I diabetes, myasthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet""s syndrome, polymyositis, gingivitis, conjunctivitis and myocardial ischemia.
Compounds of the invention are also useful in the treatment of ophthalmic diseases such as retinitis, retinopathies, uveitis and of acute injury to the eye tissue.
Compounds of the invention are also useful for the treatment of cognitive disorders such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer""s disease, Pick""s disease, Huntington""s chorea, Parkinson""s disease and Creutzfeldt-Jakob disease), and vascular dementia (including multi-infarct dementia), as well as dementia associated with intracranial space occupying lesions, trauma, infections and related conditions (including HIV infection), metabolism, toxins, anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.
According to a further aspect of the invention, we provide a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in human or veterinary medicine.
According to another aspect of the invention, we provide a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in the treatment of a condition which is mediated by COX-2.
According to a further aspect of the invention, we provide a method of treating a human or animal subject suffering from a condition which is mediated by COX-2 which comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative.
According to a further aspect of the invention, we provide a method of treating a human or animal subject suffering from an inflammatory disorder, which method comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
According to another aspect of the invention, we provide the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof for the manufacture of a therapeutic agent for the treatment of a condition which is mediated by COX-2.
According to another aspect of the invention, we provide the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof for the manufacture of a therapeutic agent for the treatment of an inflammatory disorder.
It is to be understood that reference to treatment includes both treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise.
It will be appreciated that the compounds of the invention may advantageously be used in conjunction with one or more other therapeutic agents. Examples of suitable agents for adjunctive therapy include a 5HT1 agonist, such as a triptan (e.g. sumatriptan or naratriptan); an adenosine A1 agonist; an EP ligand (e.g. an EP4 antagonist); an NMDA modulator, such as a glycine antagonist; a sodium channel blocker (e.g. lamotrigine); a substance P antagonist (e.g. an NK1 antagonist); a cannabinoid; acetaminophen or phenacetin; a 5-lipoxygenase inhibitor; a leukotriene receptor antagonist; a DMARD (e.g. methotrexate); gabapentin and related compounds; a tricyclic antidepressant (e.g. amitryptilline); a neurone stabilising antiepileptic drug; a mono-aminergic uptake inhibitor (e.g. venlafaxine); a matrix metalloproteinase inhibitor; a nitric oxide synthase (NOS) inhibitor, such as an iNOS or an nNOS inhibitor; an inhibitor of the release, or action, of tumour necrosis factor xcex1; an antibody therapy, such as a monoclonal antibody therapy; an antiviral agent, such as a nucleoside inhibitor (e.g. lamivudine) or an immune system modulator (e.g. interferon); an opioid analgesic; a local anaesthetic; a stimulant, including caffeine; an H2-antagonist (e.g. ranitidine); a proton pump inhibitor (e.g. omeprazole); an antacid (e.g. aluminium or magnesium hydroxide; an antiflatulent (e.g. simethicone); a decongestant (e.g. phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine); an antitussive (e.g. codeine, hydrocodone, carmiphen, carbetapentane, or dextramethorphan); a diuretic; or a sedating or non-sedating antihistamine. It is to be understood that the present invention covers the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in combination with one or more other therapeutic agents.
The compounds of formula (I) and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Thus, in another aspect of the invention, we provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine. Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
The compounds of formula (I) and their pharmaceutically acceptable derivatives may be formulated for administration in any suitable manner. They may, for example, be formulated for topical administration or administration by inhalation or, more preferably, for oral, transdermal or parenteral administration. The pharmaceutical composition may be in a form such that it can effect controlled release of the compounds of formula (I) and their pharmaceutically acceptable derivatives.
For oral administration, the pharmaceutical composition may take the form of, for example, tablets (including sub-lingual tablets), capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.
For transdermal administration, the pharmaceutical composition may be given in the form of a transdermal patch, such as a transdermal iontophoretic patch.
For parenteral administration, the pharmaceutical composition may be given as an injection or a continuous infusion (e.g. intravenously, intravascularly or subcutaneously). The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. For administration by injection these may take the form of a unit dose presentation or as a multidose presentation preferably with an added preservative.
Alternatively for parenteral administration the active ingredient may be in powder form for reconstitution with a suitable vehicle.
The compounds of the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
As stated above, the compounds of the invention may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
A proposed daily dosage of a compound of formula (I) for the treatment of man is 0.01 mg/kg to 500 mg/kg, such as 0.05 mg/kg to 100 mg/kg, e.g. 0.1 mg/kg to 50 mg/kg, which may be conveniently administered in 1 to 4 doses. The precise dose employed will depend on the age and condition of the patient and on the route of administration. Thus, for example, a daily dose of 0.25 mg/kg to 10 mg/kg may be suitable for systemic administration.
Compounds of formula (I) and pharmaceutically acceptable derivatives thereof may be prepared by any method known in the art for the preparation of compounds of analogous structure.
Suitable methods for the preparation of compounds of formula (I) and pharmaceutically acceptable derivatives thereof follow. In Scheme 1 and its variations, R1 to R4, n and A are as defined in formula (I) above unless otherwise stated; Hal is a halogen, such as Cl or Br; MTBE is methyl t-butyl ether; and alkyl is a straight or branched chain alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group.
Referring to Scheme 1, the treatment of compounds of formula (III) with an amine of formula (II) is conveniently carried out in a solvent, such as a nitrile (e.g. methylnitrile) and at elevated temperature (e.g. from about 50xc2x0 C. to reflux). An excess of the amine may be used in place of the solvent.
Conveniently, the boronic acid coupling shown in Scheme 1 is carried out in a solvent, such as an ether (e.g. 1,2-dimethoxyethane); in the presence of a base, such as an inorganic base (e.g. sodium carbonate); and employing a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0). 
Conveniently the oxidation shown in Scheme 1 is effected using a monopersulfate compound, such as potassium peroxymonosulfate (known as Oxone(trademark)) and the reaction is carried out in a solvent, such as an aqueous alcohol, (e.g. aqueous methanol), and at between xe2x88x9278xc2x0 C. and ambient temperature.
Referring to Scheme 1, the cyclisation of diones of formula (VI) to give the corresponding pyrimidines of formula (IV) is conveniently carried out employing a thioronium salt such as a 2-methyl-2-thiopseudourea sulfate and under reflux.
It will be appreciated by those skilled in the art that certain of the procedures described in Scheme 1 for the preparation of compounds of formula (I) or intermediates thereto may not be applicable to some of the possible substituents.
It will be further appreciated by those skilled in the art that it may be necessary or desirable to carry out the transformations described in Scheme 1 in a different order from that described, or to modify one or more of the transformations, to provide the desired compound of formula (I).
In one variation of Scheme 1 (scheme 1A), compounds of formula (III) wherein R3 is C1-6alkyl may be prepared by oxidising a disulphide of formula (IV)A: 
under oxidation conditions described hereinabove. Disulphides of formula (IV)A may be prepared according to the general procedures of Scheme 1 by employing sulphide derivatives in place of the corresponding alkylsulphonyl compounds of formulae (VII) and (VIII).
In another variation of scheme 1 (scheme 1B), compounds of formula (I) wherein R4 is H may be prepared from the corresponding formamyl derivative, as illustrated below. 
It will be appreciated by those skilled in the art that compounds of formula (I) may be prepared by interconversion, utilising other compounds of formula (I) as precursors. Suitable interconversions, such as alkylations, are well known to those skilled in the art and are described in many standard organic chemistry texts, such as xe2x80x98Advanced Organic Chemistryxe2x80x99 by Jerry March, fourth edition (Wiley, 1992), incorporated herein by reference. For example, compounds of formula (I) wherein R4 is C1-6alkyl may be prepared by alkylating the corresponding compound of formula (I) wherein R4 is H.
Acylation of compounds of formula (I) wherein R3 is NH2 to provide corresponding acylated benzenesulphonamide derivatives may be carried out by conventional means, for example by employing conventional acylating agents such as those described in xe2x80x98Advanced Organic Chemistryxe2x80x99, pp 417-424.
As will be appreciated by those skilled in the art it may be necessary or desirable at any stage in the synthesis of compounds of formula (I) to protect one or more sensitive groups in the molecule so as to prevent undesirable side reactions. The protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See, for example, those described in xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 by Theodora W Green and Peter G M Wuts, second edition, (John Wiley and Sons, 1991), incorporated herein by reference, which also describes methods for the removal of such groups.
Amines of formula (II) are either known compounds or may be prepared by literature methods, such as those described in xe2x80x98Comprehensive Organic Transformations: a guide to functional group preparationsxe2x80x99 by Richard Larock (VCH, 1989), incorporated herein by reference.
Thioronium salts of formula (V) are either known compounds or may be prepared by literature methods, such as those described in A H Owens et al, Eur J Med Chem, 1988, 23(3), 295-300, incorporated herein by reference
Acetophenones of formula (VII) are either known compounds or may be prepared by conventional chemistry.
Boronic acids of formula (VIII) or derivatives thereof are either known compounds or may be prepared by literature methods, such as those described in EPA publication No. 533268; or R Miyaura et al, J Org Chem, 1995, 60, 7508-7510; each incorporated herein by reference.
4-Halo-6-trifluoromethylpyrimidines of formula (IX) are either known compounds or may be prepared by literature methods, such as those described in Japanese Patent no. 42014952 (Chem Abs ref CAN 68:105224), incorporated herein by reference.
Alkyl halides of formula (XII) are either known compounds or may be prepared by conventional chemistry.
Certain intermediates described above are novel compounds, and it is to be understood that all novel intermediates herein form further aspects of the present invention. Compounds of formulae (III), (IV) and (XIII) are key intermediates and represent a particular aspect of the present invention.
Conveniently, compounds of the invention are isolated following work-up in the form of the free base. Pharmaceutically acceptable acid addition salts of the compounds of the invention may be prepared using conventional means.
Solvates (e.g. hydrates) of a compound of the invention may be formed during the work-up procedure of one of the aforementioned process steps.
The Intermediates and Examples that follow illustrate the invention but do not limit the invention in any way. All temperatures are in xc2x0 C. Flash column chromatography was carried out using Merck 9385 silica. Solid Phase Extraction (SPE) chromatography was carried out using Varian Mega Bond Elut (Si) cartridges (Anachem) under 15 mmHg vacuum with stepped gradient elution. Thin layer chromatography (Tlc) was carried out on silica plates. In addition to those already defined, the following abbreviations are used: Me, methyl; Ac, acyl; DMSO, dimethylsulphoxide; TFA, trifluoroacetic acid; DME, dimethoxyethane; THF, tetrahydrofuran; DCM, dichloromethane; and MTBE, methyl t-butyl ether.
Intermediate 1
4,4,4-Trifluoro-1-[4-(methylthio)phenyl]butane-1,3-dione
To a solution of ethyl trifluoroacetate (7.95 ml, 1.1 eq) in MTBE (125 ml) was added dropwise 25% sodium methoxide in methanol (16 ml, 1.2 eq). 4-Methylthioacetophenone (Aldrich, 10 g, 0.06 mol) was added portionwise and the mixture stirred at ambient temperature overnight. 2N Hydrochloric acid (40 ml) was added cautiously and the organic phase separated, washed with brine and dried (Na2SO4) to give an orange solid. The orange solid was recrystallised from hot isopropanol to give the title compound as a yellow crystalline solid (11.25 g, 71%).
MHxe2x88x92261
Intermediate 2
2-(Methylthio)-4-[4-(methylthio)phenyl]-6-(trifluoromethyl) pyrimidine
To a mixture of 4,4,4-trifluoro-1-[4-(methylthio)phenyl]butane-1,3-dione (5 g) and 2-methyl-2-thiopseudourea sulfate (5.1 g, 0.98 eq) in acetic acid (100 ml) was added sodium acetate (3 g, 2 eq) and heated under reflux for 8 h. The mixture was concentrated in vacuo and water (100 ml) added to give a solid, which was isolated by filtration to give the title compound as a yellow solid (5.8 g, quantitative).
MH+317
Intermediate 3
2-(Methylthio)-4-[4-(methylthio)phenyl]-6-(trifluoromethyl) pyrimidine
A mixture of 4-chloro-2-methylthio-6-(trifluoromethyl)pyrimidine (ButtPark Ltd, 2.86 g, 14.55 mmol), 4-(methylthio)phenylboronic acid (Aldrich, 2.83 g, 1.1 eq), tetrakistriphenylphosphine palladium (0) (0.2 g) and sodium carbonate (4.04 g, 2.6 eq) in DME (200 ml) and water (100 ml) was heated under reflux with stirring under N2 for 24 h. The reaction mixture was concentrated in vacuo and the resultant mixture partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried (Na2SO4) and concentrated in vacuo to a purple solid. Purification by flash column chromatography with cyclohexane:ethyl acetate as (6:1) as eluant gave the title compound as a yellow crystalline solid (3.86 g, 84%).
MH+317
Tlc SiO2 cyclohexane:ethyl acetate (3:1) Rf 0.75 uv254 
Intermediate 4
2-(Methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine
To a solution of 2-(methylthio)-4-[4-(methylthio)phenyl]-6-(trifluoromethyl) pyrimidine (5.78 g) in MeOH (500 ml) was added a solution of OXONE(trademark) (Aldrich, 56.23 g, 5 eq) in water (200 ml). The mixture was stirred at ambient temperature overnight, concentrated in vacuo and the residue partitioned between water and ethyl acetate (2xc3x97100 ml). The combined organic phases were dried and concentrated in vacuo to an off-white solid which was triturated with hot isopropanol to give the title compound as a white solid (5.6 g, 80%).
MH+381
Tlc SiO2 Ethyl acetate:cyclohexane (1:1) Rf 0.45
Intermediate 5
4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-amine
A solution of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (2 g, 5.258 mmol) in acetonitrile (30 ml) was treated with 0.880 ammonia (6 ml) dropwise. The resulting mixture was then stirred at 20 C. for 18 h. This gave the title compound as a colourless precipitate which was collected by filtration and dried (1.53 g)
MHxe2x88x92=316
Intermediate 6
4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-ylformamide
A mixture of formic acid (7 ml) and acetic anhydride (2 ml) was stirred at 20 C for 1 h. 4-[4-(Methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-amine (0.5 g, 1.576 mmol) was then added and stirring was continued at ambient temperature for 18 h. This gave the title compound as a colourless precipitate which was collected by filtration and dried (0.32 g).
MH+=346
Intermediate 7
(5-methyl-1H-imidazol-4-yl)methyl[4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2yl]formamide
To a stirred solution of 4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-ylformamide (0.5 g, 1.54 mmol) in dry dimethylformamide (10 ml) under N2 was added sodium hydride (60% dispersion in oil, 0.16 g). The mixture was stirred for 30 mins, 4-(chloromethyl)-5-methyl-1H-imidazole, hydrochloride (0.283 g) was added and stirring was then continued at room temp for 18 h. The mixture was then partitioned between water and ethyl acetate. The extracts were dried (Na2SO4) and evaporated. The residue was then triturated with diethyl ether giving the crude title compound as a pale yellow solid (0.27 g).
MH+=440